A Japanese Trial of TH-302 in Subjects With Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma

A Phase II, Single-arm, Japanese Multicenter Trial of TH-302 in Combination With Doxorubicin in Subjects With Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma

This is a Phase 2, single-arm, Japanese multicenter trial to evaluate the safety, tolerability, and efficacy of TH-302 in combination with doxorubicin in subjects with locally advanced unresectable or metastatic soft tissue sarcoma (STS).

Inclusion Criteria:

• Male or female Japanese subjects greater than or equal to (>=) 15 years of age
• Able to understand the purposes and risks of the trial and has signed or, if appropriate, the subject's parent or legal guardian has signed a written informed consent form approved by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC)
• Pathologically confirmed diagnosis of STS of the histopathologic types as specified in the protocol
• Locally advanced unresectable or metastatic disease with no standard curative therapy available and for whom treatment with single agent doxorubicin is considered appropriate
• Recovered from reversible toxicities of prior therapy
• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (at least one target lesion outside of previous radiation fields or progressed within a previous radiation field)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy of at least 3 months
• Acceptable liver function, renal function, hematologic status (without growth factor support for neutropenia or transfusion dependency), and cardiac function as specified in the protocol
• All women of childbearing potential must have a negative serum pregnancy test and all subjects must agree to use effective means of contraception (surgical sterilization or the use of barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an intrauterine device, intrauterine device [IUD]) with their partner from entry into the trial through 6 months after the last dose. Post-menopausal women must meet the criteria of 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels greater than (>) 35 international units per liter (IU/L)

Exclusion Criteria:

• Low grade tumors according to standard grading systems (for example, American Joint Committee on Cancer [AJCC] Grade 1 and 2 or Fédération Nationale des Centres de Lutte Contre le Cancer [FNCLCC] Grade 1)
• Prior systemic therapy for advanced or metastatic STS (neoadjuvant therapy followed by surgical resection and adjuvant therapy permitted)
• Prior STS therapy with ifosfamide or cyclophosphamide or other nitrogen mustards; prior systemic therapy with an anthracycline or anthracenedione; or prior mediastinal/cardiac radiotherapy
• Current use of drugs with known cardiotoxicity or known interactions with doxorubicin
• Anti-cancer treatment with radiation therapy, neoadjuvant or adjuvant chemotherapy, targeted therapies, immunotherapy, hormones or other antitumor therapies within 4 weeks prior to trial entry (6 weeks for nitrosoureas or mitomycin C).
• Significant cardiac dysfunction precluding treatment with doxorubicin as specified in the protocol
• Seizure disorders requiring anticonvulsant therapy unless seizure-free for the last year
• Known brain metastases (unless previously treated and well controlled for a period of >=3 months before screening)
• Previously diagnosed malignancies, except for adequately treated non-melanoma skin cancer, in situ cancer, or other cancer from which the subject has been disease-free for at least 5 years before screening
• Severe chronic obstructive or other pulmonary disease with hypoxemia (requires supplementary oxygen, symptoms due to hypoxemia or oxygen saturation <90% by pulse oximetry after a 2 minute walk) or in the opinion of the investigator any physiological state likely to cause normal tissue hypoxia
• Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without complete recovery
• Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
• Prior therapy with a hypoxic cytotoxin
• Subjects who participated in an investigational drug or device trial within 28 days prior to trial entry
• Known infection with human immunodeficiency virus (HIV) or active infection with hepatitis B or hepatitis C
• Subjects who have exhibited allergic reactions to a structural compound similar to TH-302 or the drug product excipients
• Subjects who are taking medications that prolong QT interval and have a risk of Torsades de Pointes
• Subjects with a corrected QT (QTc) interval calculated according to Bazett's formula of >450 milliseconds (msec) based on a screening electrocardiogram (ECG)
• Subjects with a history of long QT syndrome
• Subjects taking a medication that is a moderate or strong inhibitor or inducer of cytochrome P450 3A4 (CYP3A4)
• Females who are pregnant or breast-feeding
• Concomitant disease or condition that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study
• Unwillingness or inability to comply with the study protocol for any reason
• Legal incapacity or limited legal capacity